Cell cycle (CC) and TP53 regulatory networks are frequently deregulated in cancer. While numerous genome-wide studies of TP53 and CC-regulated genes have been performed, significant variation between studies has made it difficult to assess regulation of any given gene of interest. To overcome the limitation of individual studies, we developed a meta-analysis approach to identify high confidence target genes that reflect their frequency of identification in independent datasets. Gene regulatory networks were generated by comparing differential expression of TP53 and CC-regulated genes with chromatin immunoprecipitation studies for TP53, RB1, E2F, DREAM, B-MYB, FOXM1 and MuvB. RNA-seq data from p21-null cells revealed that gene downregulation by TP53 generally requires p21 (CDKN1A). Genes downregulated by TP53 were also identified as CC genes bound by the DREAM complex. The transcription factors RB, E2F1 and E2F7 bind to a subset of DREAM target genes that function in G1/S of the CC while B-MYB, FOXM1 and MuvB control G2/M gene expression. Our approach yields high confidence ranked target gene maps for TP53, DREAM, MMB-FOXM1 and RB-E2F and enables prediction and distinction of CC regulation. A web-based atlas at www.targetgenereg.org enables assessing the regulation of any human gene of interest.

Chapter 1 Summary of the Dissertation "We are in the golden age of fraud." Jim Chanos, Kynikos Associates, Financial Times 24/07/2020. Beyond the speculations about the consecutive waves of Covid, 2020 will be reminded for one of the most notorious failures of a listed firm, due to a massive accounting fraud: the German payment fintech Wirecard. The firm, with 30 subsidiaries in 26 countries, joined the prestigious DAX index just two years before. The spillovers of the billion-euro fraud range from the arrest of top managers to suspicion of auditors, politicians, and regulatory authorities (BaFin, European Commission, and ESMA), as suggested the Financial Times headline "Why was Frankfurt so blind for so long?"1 Such a failure serves as a reminder of the relevance of financial markets regulation, oversight, and enforcement, in order to protect investors and to encourage compliance with regulations. Research on the relationship between the publication of financial misconducts and financial performance for corporates has continuously grown, as illustrated by the recent in- depth literature reviews undergone by Amiram et al. (2018) and Liu and Yawson (2020). It is fueling regulatory debates on how to enforce more efficiently financial regulations. Some specificities of white-collar crimes must be accounted for...

Objective: A systematic review and meta-analysis was performed to evaluate the safety and efficacy of drug-eluting stents (DES) vs bare-metal stents (BMS) in atrial fibrillation (AF) patients. Methods: We systematically searched 5 engines until May 2019 for cohort studies and randomized controlled trials (RCTs). Primary outcomes were major bleeding and major adverse cardiac events (MACE) including cardiac death, myocardial infarction, target vessel revascularization (TVR) or stent thrombosis. Effects of inverse variance random meta-analyses were described with relative risks (RR) and their 95% confidence intervals (CI). We also stratified analyses by type (triple [TAT] vs dual [DAT]) and duration (short-vs long-term) of antithrombotic therapy. Results: Ten studies (3 RCTs; 7 cohorts) including 10,353 patients (DES: 59.6%) were identified. DES did not show higher risk of major bleeding than BMS (5.6% vs 6.9%, RR 1.07; 95%CI, 0.89–1.28, p = 0.47; I2 = 0%) or MACE (12% vs 13.6%; RR 0.96; 95%CI 0.81–1.13, p = 0.60; I2 = 44%). Although, DES almost decreased TVR risk (6.4% vs 8.4%, RR 0.78; 95%CI, 0.61–1.01, p = 0.06; I2 = 15%). Stratified analyses by type and duration of antithrombotic therapy showed no differences in major bleeding or MACE between both types of stents. In DES, long-term TAT showed higher major bleeding risk than long-term DAT (7.7% vs 4.7%, RR 1.48, 95%CI 1.08–2.03, p = 0.01; I2 = 12%). For both types of stents, MACE risk was similar between TAT and DAT. Conclusions: In patients with AF undergoing PCI, DES had similar rate of major bleeding and MACE than BMS. DAT seems to be a safer antithrombotic therapy compared with TAT. / Janssen Pharmaceuticals / Revisión por pares

The dissertation consists of three papers presenting applications of meta-analysis in economics and introductory chapter which discusses the development of meta-analysis in author's perspective as well as strengths and weaknesses of this quantitative method to synthesize empirical research. In the first paper analyses the impact of information and communication technology investments on productivity. The second paper focuses on the trade effect of the euro. In the third investigates the relation between international trade flows and trade costs.

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Genetic association studies have successfully identified many genetic markers associated with complex human diseases and related quantitative traits. However, for most complex diseases and quantitative traits, all associated genetic markers identified to date only explain a small proportion of heritability. Thus, exploring the unexplained heritability in these traits will help us discover novel genetic determinants for these traits and better understand disease etiology and pathophysiology. Due to limited sample size, a single cohort study may not have sufficient power to identify novel genetic association with a small effect size, and meta-analysis approaches have been proposed and applied to combine results from multiple cohorts in large consortia, increasing the sample size and statistical power. Rare genetic variants and gene by environment interaction may both play a role in genetic association studies. In this dissertation, we develop statistical methods in meta-analysis, rare genetic variants analysis and gene by environment interaction analysis, conduct extensive simulation studies, and apply these methods in real data examples. First, we develop a method of moments estimator for the between-study covariance matrix in random effects model multivariate meta-analysis. Our estimator is the first such estimator in matrix form, and holds the invariance property to linear transformations. It has similar performance with existing methods in simulation studies and real data analysis. Next, we extend the Sequence Kernel Association Test (SKAT), a rare genetic variants analysis approach for unrelated individuals, to be applicable in family samples for quantitative traits. The extension is necessary, as the original test has inflated type I error when directly applied to related individuals, and selecting an unrelated subset from family samples reduces the sample size and power. Finally, we derive methods for rare genetic variants analysis in detecting gene by environment interaction on quantitative traits, in the context of univariate test on the interaction term parameter. We develop statistical tests in the settings of both burden test and SKAT, for both unrelated and related individuals. Our methods are relevant to genetic association studies, and we hope that they can facilitate research in this field and beyond.

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BACKGROUND: Posterior inferior cerebellar artery (PICA) aneurysms are an uncommon, heterogeneous group of aneurysms with poorer neurological outcomes compared to other intracranial aneurysms. At first, as part A, we conducted a systematic review of the literature to evaluate the safety and efficacy of treatment strategies for PICA-aneurysms. Subsequently, as part B, we performed a multicenter retrospective study to analyze the outcome in a large series of patients treated with contemporary microsurgical and endovascular techniques. METHODS: For the meta-analysis, a systematic search of Medline, EMBASE, Scopus and Web of Science was done for studies published through November 2015. We included studies that described treatment of PICA-aneurysms with ≥10 patients. Random-effects meta-analysis was used to pool the following outcomes: complete occlusion, technical success, periprocedural morbidity/mortality, stroke rates, aneurysm recurrence/rebleed, CN-palsies rates, and long-term neurological morbidity/mortality. As the second part, aiming to report the current trends and results in treatment strategies for PICA-aneurysms, records of 94 patients treated for PICA-aneurysms between 2000 and 2015 at 3 large referral neurovascular centers were retrospectively reviewed. RESULTS: In the meta-analysis, we...

The relationship between income inequality and happiness is central to a host of welfare policies. If higher income inequality puts people down, advocating for income redistribution from the rich to the poor could make society happier. We show, however, that this popular consensus on the relationship's direction is rather absent in the academic literature. Based on the 868 observations col- lected from 53 studies and controlling for 62 aspects of study design, we use state-of-the-art meta-analysis techniques to identify several important drivers of the efect. Unless each study gets the same weight, the literature is driven by publication bias pushing the estimates against the popular consensus. While geographical diferences dominate among the systematic infuences of the re- lationship's magnitude, the relationship is also strongly afected by various methods and data the authors use in the primary studies. Most prominently, it matters if authors control for diferent individual's characteristics, such as perceived trust in people or their health status.

The endemic eelgrass (Zostera marina) community of Morro Bay Estuary, located on the central coast of California, has experienced an estimated decline of 95% in occupied area (reduction of 344 acres to 20 acres) from 2008 to 2017 for reasons that are not yet definitively clear. One possible driver of degradation that has yet to be investigated is the role of herbicides from agricultural fields in the watershed that feeds into the estuary. Thus, the primary research goal of this project was to better understand temporal and spatial trends of herbicide use within the context of San Luis Obispo (SLO) County and Morro Bay Watershed by analyzing data of application by mass, area, and intensity to identify herbicides with the highest potential for local environmental pollution. California Pesticide Use Annual Summary Reports (PUASR) from the years 2000 to 2017 were used to obtain data for conducting a meta-analysis to estimate total herbicide application by weight within every township, range, and section for each of the eight selected herbicides: oxyfluorfen, glyphosate, diuron, chlorthal-dimethyl, simazine, napropamide, trifluralin, and oryzalin. A second goal was to select an analytical laboratory that would be best suited for herbicide analysis of estuary sediments to determine the presence, or lack thereof, of the eight selected herbicides. Criteria of consideration in laboratory selection included herbicides detection capabilities, detection/reporting limits, testing prices, chain of custody protocols, turnaround times, and laboratory site locations. The meta-analysis yielded results showing high herbicide application rates in SLO County with glyphosate, oxyfluorfen, and chlorthal-dimethyl being identified as three herbicides of elevated risk for local environmental contamination due high rates of use by mass, by area, and/or intensity during the study timeframe. Additionally, Morro Bay Watershed exhibited moderate rates of herbicide application with chlorthal-dimethyl and glyphosate being of highest risk for contamination and accumulation within the estuary because of high application rates by mass, by area, and/or intensity. Finally, Environmental Micro Analysis (EMA) and Primus Group, Inc. (PrimusLabs) were identified as the top candidates for analytical laboratory testing of Morro Bay Estuary sediment samples to be obtained and tested for the selected herbicides. These laboratories provide superior analytical capabilities of the eight herbicides, impressive reporting limits or lower detection limits, competitive testing prices for detecting multiple constituents in multiple samples, robust chain of custody protocols, options for quick turnaround times, and laboratory site locations within California.